A Study of the Short-Term Effect of Artificial Tears on Contrast Sensitivity in Patients With Sjögren's Syndrome

Abstract

Purpose.: Primary Sjögren's syndrome often includes dry eye manifestations, including a reduction in optical quality from the compromised ocular surface. This study was designed to measure the effect of different artificial tears on the contrast sensitivity of Sjögren's syndrome patients from 5 minutes to 4 hours after instillation.

Methods.: Ten normal subjects and 10 subjects with ocular manifestations of Sjögren's syndrome were compared at baseline, including staining scores, a dry eye questionnaire, and contrast sensitivity testing. Changes in contrast sensitivity in the Sjögren's syndrome group were measured over a 4-hour period after instillation of a variety of artificial tears.

Results.: Statistically significant differences in staining, subjective questionnaire scores, and contrast sensitivity were measured between the normal and Sjögren's syndrome groups. Statistically significant changes in contrast sensitivity were measured over time after artificial tear instillation, with the greatest effect at 3 to 6 cycles/deg. The more mucoadhesive artificial tears demonstrated a significantly greater effect.

Conclusions.: The effects of artificial tears on measured contrast sensitivity in dry eye patients in the postinstillation period of 5 minutes to 4 hours appear limited, but an artificial tear with more mucoadhesive properties showed more benefit than those that do not. Modest effects on contrast sensitivity, primarily at medium spatial frequencies, were observed with the more mucoadhesive formulations.

Introduction

Primary Sjögren's syndrome (SS) is characterized by lymphocytic infiltration of different exocrine and nonexocrine epithelia. ¹ Dry eye is the hallmark ocular manifestation and a key diagnostic characteristic. ² The dry eye is attributable to aqueous deficiency caused by degeneration of the lacrimal gland. The end result of the chronic dry eye is a compromised ocular surface, ³ with associated changes in vision ^4,5 and vision-related quality of life. ⁵  

Relevant to the current study, dry eye is known to reduce the level of visual function and increase the variability in visual function. ⁴ This is manifested in the measurement of contrast sensitivity in normal and dry eye groups. ^6,7  

Numerous therapies are designed to alleviate the effects of moderate dry eye, the most common being the use of artificial tears as needed, primarily to improve ocular comfort. The residence time of such solutions varies with their particular composition. ⁸ Measures of visual quality after instillation of artificial tears have been concerned primarily with the negative impact of the tears immediately after instillation. ^7,9 Studies measuring improvements in contrast sensitivity typically have tested subjects in a very short time period (e.g., 10 minutes or less). ^6,10 Longer term (weeks) effects of artificial tear instillation have been studied, and improvements in contrast sensitivity noted. The reason for this improvement has not been determined to our knowledge, but does not appear related to changes in the ocular surface. ⁷  

Residence time, the time that an artificial tear appears to remain on the eye, is a factor that influences the frequency of use. More recent artificial tear formulations have been designed to try to increase this residence time. ¹¹ With longer residence times, the measured effect on visual function also may be longer. 

Our study was designed to evaluate the effect of various over-the-counter artificial tear products on functional vision in subjects with dry eye associated with Sjögren's syndrome. Functional vision was evaluated using a contrast sensitivity test; measurements were made from 5 minutes to 4 hours after artificial tear instillation. The intent was to provide data related to expected changes in contrast sensitivity over time, and the appropriate length of time to measure such changes. 

Methods

Local ethic review board approval was applied for and obtained before the study began. Patients with known Sjögren's syndrome were identified from clinical files and recruited for the study until a total of 10 subjects was enrolled (SS group). In a similar fashion, a group of 10 normal subjects also was recruited and enrolled. The normal subjects were matched to the subjects with Sjögren's syndrome by age and sex (normal group). All recruited subjects read and signed an information and consent form before participating in the study. All subjects were treated in accordance with the Declaration of Helsinki. 

To reduce possible confounding effects, subjects with lacrimal plugs, evident punctal occlusion from other causes, or a history of contact lens wear were excluded from the study. Patients with previous eye surgery, including refractive surgery, or relevant ocular pathology (excepting SS) also were excluded. All subjects had a best corrected acuity of at least 1.0 (20/20). 

Baseline measures of dry eye were taken for both groups, to confirm the diagnosis of dry eye in the SS group. These measures included tear breakup time (TBUT), the extent of rose bengal and fluorescein staining, and a subjective questionnaire—a Chinese translation of the Ocular Surface Disease Index (OSDI). The OSDI is a validated questionnaire for measuring the severity of dry eye disease. ¹²  

All subjects in both groups had baseline contrast sensitivity (CS) tested using the Functional Acuity Contrast Test (FACT), a contrast sensitivity test included in the OPTEC 6500 Contrast Sensitivity View-in Tester (Stereo Optical Company, Inc., Chicago, IL). After baseline testing in the SS group, a drop of Systane Ultra (Alcon Laboratories, Fort Worth, TX) was instilled in the eye and contrast sensitivity was retested at 5 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after installation. The technician testing CS was masked as to which drop was instilled. Contrast sensitivity was measured at a number of different spatial frequencies, from 1.5 to 18 cycles/deg (cpd). 

The SS group returned on 3 separate occasions after the initial visit, 7 days apart, which was considered sufficient for any required washout. On subsequent visits, the contrast sensitivity was tested before drop instillation, and 5 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after instillation. The drops instilled each week were Systane Ultra (polyethylene glycol 400 0.4%, propylene glycol 0.3%, with HP Guar; Alcon Laboratories), ocular saline solution, Refresh Plus (carboxymethylcellulose sodium 0.5%; Allergan, Irvine, CA), and Hycosan (sodium hyaluronate 0.1%; Ursapharm, Arzneimittel GmbH, Saarbrücken, Germany), in that order. Given the washout period and the short time of the measurements, randomization was not considered necessary. To avoid subsequent use of brand names, they are referred to as SU, Saline, RP, and H in the remainder of this study. 

Differences in baseline data from the first visit were compared between the normal and SS group using Student's t-test. Differences in baseline contrast sensitivity also were compared using an ANOVA with two factors (spatial frequency and group). Where overall statistically significant differences were reported, post hoc analysis was performed using Tukey's honestly significant difference (HSD) test. 

The effects of the artificial tears on the contrast sensitivity of the SS group also were analyzed using appropriate techniques. Initial analysis was conducted using time as a repeated measures variable. In this way, random effects from the variability of contrast sensitivity between visits were eliminated; the repeated measures analysis was based on the change from the baseline recorded just before the artificial tears were instilled. Initial testing was performed using ANOVA. Statistically significant differences were investigated further using Tukey's HSD test, with measured differences from baseline being the critical effect. 

Finally, for those times and frequencies where a significant increase in contrast sensitivity was noted, the average contrast sensitivity measure at that time and frequency was compared to the baseline contrast sensitivity in the normal group at the same frequency. This was a measure of whether the artificial tear provided the SS group subject with relatively normal contrast sensitivity. This was performed using a series of independent t-tests. 

Statistical analyses were performed using the Statistica data analysis software system, Version 10 (StatSoft, Inc., Tulsa, OK). Parametric variables were tested using t-tests and ANOVAs with a significance set at P < 0.05. 

Results

Baseline demographics of the 10 subjects in the SS group were compared to those of the normal group. Table 1 contains the summary of these results. There was no statistically significant difference in age or sex between the groups, so matching appeared to be successful. The 5 measures of dry eye (OSDI, rose bengal and fluorescein staining, Schirmer's test, and TBUT) all were statistically significantly different between groups, with the SS group demonstrating test results consistent with the diagnosis of dry eye. 

Table 1

 

Demographic Comparison and Baseline Data

	SS Group		Normal Group		P Value
	Mean	SD	Mean	SD
Sex	8 F/2 M		8 F/2 M		1
Age	39.1	5.6	35.7	7.1	>0.25
OSDI, baseline	42.7	20.3	4.4	7.0	<0.001
NaFl staining	2.3	1.8	0.0	0.0	<0.001
Rose bengal staining	3.0	1.3	0.0	0.0	<0.001
Schirmer's test, mm	1.2	1.6	19.7	6.7	<0.001
TBUT	1.5	1.6	11.9	1.3	<0.001

The baseline contrast sensitivity of the SS group also was compared to that of the normal group. Results are shown in Figure 1. The baseline measures for the SS group are shown by visit (artificial tear). There was a statistically significant difference in baseline CS between the SS groups and the normal group at all frequencies (P < 0.01). There was no statistically significant difference between the 4 baseline visits in the SS group at any spatial frequency (P > 0.12) and no interaction effect (P > 0.21). The difference between the measured CS values for the SS and normal groups was highest for the middle spatial frequencies (i.e., 3 and 6 cpd), and lower for the high and low spatial frequencies. 

Figure 1

 

Baseline contrast sensitivity data. Vertical bars denote 0.95 confidence intervals.

Each of the artificial tears was evaluated separately, but in a similar fashion. A repeated measures ANOVA over time was performed for each artificial tear at each frequency. Table 2 contains the summary results of those tests; significantly different values (P < 0.05) are shown by asterisks. The importance of this summary table is that, for a given artificial tear, it is only relevant to analyze those spatial frequencies that show a statistically significant difference over time. There are two things to note from Table 2. The first is that the spatial frequency of 3 cpd shows the greatest improvement with all of the artificial tears. This is not surprising given that, as noted above, the difference between the SS and normal groups was highest at this frequency. The second is that the H and SU artificial tears showed the greatest effect over multiple spatial frequencies. 

Table 2

 

Repeated Measures Summary by Frequency and Group

Artificial Tear	Spatial Frequency, cycles/deg
	1.5	3	6	12	18
H	0.386	0.000*	0.003*	0.001*	0.003
RP	0.429	0.001*	0.003*	0.950	0.865
Saline	0.287	0.036*	0.409	0.749	0.002*
SU	0.013*	0.001*	0.024*	0.025*	0.148

*   P value of repeated measures ANOVA (time), significant differences.

Graphing all the results would be helpful, but excessive. However, Figure 2 provides an example of the change in contrast sensitivity over time for the different artificial tears at the most-affected spatial frequency (3 cpd). Results in Table 2 indicated that all of the artificial tears had statistically significant changes over time at that spatial frequency. However, they differed in relative performance. In the case of RP, for instance, there was a statistically significant difference between baseline and 5 minutes, but then no difference from baseline at the longer time periods. In the case of SU, there was a statistically significant change and it appeared to be sustained over the 4-hour time period. 

Figure 2

 

Change in contrast sensitivity over time by artificial tear at spatial frequency of 3 cpd. Vertical bars denote 0.95 confidence intervals.

Table 3 contains a summary of the results from Tukey's HSD test, which allowed a more detailed post hoc analysis of the changes over time by frequency than were reported in Table 2. The changes in the FACT contrast sensitivity score by artificial tear, time, and spatial frequency are shown, with those changes that are statistically significantly different from the baseline value noted by asterisks. The most significant changes appeared to be at 3 cpd, where all artificial tears but Saline had a statistically significant difference from baseline at 5 minutes, and tears H and SU demonstrated a significant difference for 2 hours or more. 

Table 3

 

Change in FACT Contrast Sensitivity Score by Tear, Time, and Spatial Frequency

Artificial Tear	Minutes After Instillation	Spatial Frequency, cycles/deg
		1.5	3	6	12	18
H	5	4.6 ± 9.7	22.8 ± 16.2*	15.2 ± 20.4*	9.3 ± 10*	3.3 ± 2.4*
H	30	3.2 ± 11.3	29.1 ± 22.8*	19.7 ± 19.1*	4.1 ± 8.9	3.2 ± 4.9*
H	60	0 ± 7.4	24.5 ± 14.5*	6.6 ± 15.2	1 ± 9	0.4 ± 2.5
H	120	1.1 ± 7.5	18.2 ± 16.4*	6.9 ± 10.7	−1 ± 10.3	0.6 ± 3.1
H	240	2.8 ± 8.2	5.1 ± 16.3	3.1 ± 6.7	−2.7 ± 4.6	0.3 ± 2.2
RP	5	−3.5 ± 12.2	21.7 ± 18.4*	19.9 ± 17.1	−1.7 ± 8.2	−0.8 ± 5
RP	30	4.7 ± 8.4	4 ± 12.1	2.1 ± 21.5	−1.5 ± 7.7	0.4 ± 4.2
RP	60	0.9 ± 9.3	5.1 ± 8.7	−6.4 ± 20.8	−0.4 ± 5.7	0.6 ± 5.1
RP	120	−0.9 ± 13.2	2.8 ± 12.4	−4.5 ± 16	−2.1 ± 6.8	−0.2 ± 4.2
RP	240	1.7 ± 16.3	4.5 ± 15.4	−6.4 ± 20.8	−1.5 ± 3.6	0.3 ± 4.5
Saline	5	5.4 ± 7.2	14.3 ± 26.2	6.6 ± 23.9	2.2 ± 6	5.6 ± 5.6*
Saline	30	1.9 ± 14.7	7.5 ± 20.5	1.6 ± 26.2	0.6 ± 5.3	4.7 ± 4.1*
Saline	60	−2.2 ± 17.9	−6.2 ± 21.5	−4.1 ± 21.9	0.3 ± 5.8	2.4 ± 4.6
Saline	120	−0.7 ± 13.4	2.9 ± 16.1	0.4 ± 18.2	0.1 ± 5.4	3.1 ± 5.2
Saline	240	−4.3 ± 13.9	0.6 ± 9.5	−6.2 ± 16.4	−0.1 ± 4.8	2.4 ± 5.1
SU	5	20.2 ± 13*	41.5 ± 21.1*	29.8 ± 18.3	13.2 ± 12.4*	7.2 ± 10
SU	30	11.4 ± 8	34.1 ± 24.3*	27.9 ± 19.1	7.9 ± 9.6	4.4 ± 3.9
SU	60	16 ± 8.3*	48.4 ± 39.1*	35.9 ± 31.7*	6.3 ± 11.6	5.4 ± 4.9
SU	120	10.2 ± 14.5	37.5 ± 31.4*	30.7 ± 35.2	6.8 ± 10.3	4 ± 5.1
SU	240	12.6 ± 23	32.4 ± 32.3	37 ± 52.8*	−0.2 ± 6	5.1 ± 6.3

*  Statistically significant differences from baseline are shown.

Only SU appeared to affect CS significantly at the lowest spatial frequency. Tears SU and H demonstrated significant effect at the most different frequencies, and appeared to have the longest effects. Tear RP had only one significant effect, improving CS at 3 cpd at 5 minutes. The effect of Saline was limited to the highest spatial frequency, 18 cpd, where a significant improvement in CS was observed for the first 30 minutes. 

Table 4 contains the difference in FACT contrast sensitivity score by tear, time, and spatial frequency for the 22 tear, time, and frequency combinations that were statistically significantly better than baseline (from Table 3). In this instance, we were interested in a P value >0.05, as that would suggest that there was no statistically significant difference between the baseline value measured for the normal group and the SS group at that time, with that artificial tear, at that spatial frequency. As can be seen, only 2 values met this criterion: SU at 5 minutes at a spatial frequency of 1.5 cpd and SU at 60 minutes at a spatial frequency of 3.0 cpd. In general, even though statistical significance may not have been achieved, a higher P value suggested that the eye is “closer to normal” than the lower P values. 

Table 4

 

Difference in FACT Contrast Sensitivity Score by Tear, Time, and Spatial Frequency (compared to baseline normal group)

Artificial Tear	Min After Instillation	Spatial Frequency, cycles/deg	Control CS*		Test CS		P Value†
			Mean	SD	Mean	SD
H	5 min	3	130.6	34.19	82.8	26.91	0.003
H	5 min	6	120.4	33.86	72.5	33.04	0.005
H	5 min	12	66.6	29.89	38	21.02	0.023
H	5 min	18	29	17.45	12	5.19	0.008
H	30 min	3	130.6	34.19	89.1	28.39	0.008
H	30 min	6	120.4	33.86	77	25.45	0.004
H	30 min	18	29	17.45	11.9	6.76	0.01
H	60 min	3	130.6	34.19	84.5	17.12	0.001
H	2 h	3	130.6	34.19	78.2	29.1	0.002
RP	5 min	3	130.6	34.19	95.9	29.57	0.025
Saline	5 min	18	29	17.45	9.6	4.67	0.003
Saline	30 min	18	29	17.45	8.7	3.89	0.002
SU	5 min	1.5	62.1	24.6	44.7	15.65	0.075
SU	5 min	3	130.6	34.19	94.7	21.47	0.011
SU	5 min	12	66.6	29.89	35.8	17.06	0.011
SU	30 min	3	130.6	34.19	87.3	26.29	0.005
SU	60 min	1.5	62.1	24.6	40.5	13.89	0.026
SU	60 min	3	130.6	34.19	1016	37.5	0.087
SU	60 min	6	120.4	33.86	74.1	32.97	0.006
SU	2 h	3	130.6	34.19	90.7	38.1	0.024
SU	4 h	3	130.6	34.19	85.6	39.17	0.013
SU	4 h	6	120.4	33.86	75.2	54.5	0.039

*  Control CS is the baseline normal group average at the given spatial frequency.

†   P > 0.05 is of interest, as it suggests CS is similar between the baseline normal and SS groups at that tear/time/spatial frequency.

Discussion

Our study investigated the differences in contrast sensitivity between normal subjects and subjects with dry eye related to Sjögren's syndrome, and whether the use of artificial tears can improve contrast sensitivity in the short term, defined here as 5 minutes to 4 hours after instillation. Previous researchers have shown that the instillation of artificial tears and ophthalmic solutions can affect contrast sensitivity negatively in the immediate postinstillation period (measured in seconds), but corresponding improvements after that time period were not measured. ^9,10,13,14 Recent efforts also have been directed to the effects of artificial tears on the timing of TBUT, but these have not measured any associated effects on vision. ¹⁵ Additional research has demonstrated that degradation in visual acuity may be delayed for a time longer than the TBUT for some particular artificial tear compositions; in this case the best performance was seen in a tear with the same active ingredients as the SU used here. ¹⁶  

The objective results observed in our study suggested that any effect of artificial tears on contrast sensitivity is limited in nature, in terms of the length of effect and the relative improvement in the shorter term. The greatest improvement was seen at 3 cpd, a medium spatial frequency that corresponds to the highest contrast sensitivity in normal eyes (see Fig. 1). It is possible that at the higher and lower spatial frequencies the differences in performance are too small, and/or the variability in the measurements too great, to provide definitive clinical data. Note that two of the artificial tears (H and SU) did show a modest effect at other spatial frequencies, though for a shorter period of time. While limited, any improvement in visual function is likely to be appreciated by patients. Longer term effects, from improved health of the ocular surface, were not studied. 

There were only two measured values where the contrast sensitivity was not statistically significantly different from the normal group, both evident with SU at 3 cpd. This suggested that artificial tears, at least at the time of instillation, are unlikely to provide “normal” contrast sensitivity to patients with dry eye. However, the “near normal” effect of SU in these few instances, and the results shown in Table 3, suggested SU has properties that provide better contrast sensitivity improvement than the other artificial tears tested at 3 and 6 cpd up to 4 hours after instillation. 

The contrast sensitivity function of the human eye peaks around the spatial frequencies from 3 to 6 cpd; one is most visually sensitive to seeing objects and information contained in objects around that range of spatial frequencies. Larger and smaller objects generally need more contrast to be seen. The most significant relationship between contrast sensitivity and the visibility of complex objects occurs at the peak of the contrast sensitivity function. ¹⁷ As such, changes in contrast sensitivity at this peak frequency can have a significant effect on overall visual quality. 

The change in overall visual performance from an improvement in the 3 cpd range of contrast sensitivity may be limited. Reading and finer resolution tasks, not surprisingly, depend more on high spatial frequencies. ¹⁸ However, facial recognition may be improved, as it depends more on low to middle spatial frequencies. ¹⁹ There also is likely to be some improvement in the subjective quality of vision perceived, but this was not investigated here. Subsequent testing might consider use of a subjective quality of vision score over time, to determine if any objective changes in contrast sensitivity at specific frequencies improve a subject's overall perception of their visual quality. The reasons for intermediate spatial frequencies being most affected by artificial tears have not been elucidated. There is good evidence that ocular aberrations are significantly affected by tear breakup, ²⁰ but more detailed information is lacking. It is worth noting that the improvement in the ocular surface is implicated in these improvements in aberrations in the short term. 

The artificial tear SU, then, may produce a longer effect based on greater interaction with the corneal epithelium, so that between tears there still is some surface coverage that works to improve optical quality. Previous research into the effects of the constituents in SU have demonstrated an apparently greater adherence to the corneal epithelium than has been observed in compounds, such as saline or RP. The inclusion of HP Guar often is stated to improve attachment to the corneal epithelium, and clinical evidence has shown that it acquires the properties of a gel in vitro, matching in vivo test results. ²¹ The mechanism of action of the active ingredients is described by Springs. ²² Tear H has a similar, but lower, affinity for the epithelium, and it was observed to be the second-most effective artificial tear tested here. 

Muco-adhesion appears to be a major, but not the only, factor in residence time of artificial tears and is affected by the specific formulation. ¹¹ Increased tear-film break-up time also has been observed with increased muco-adhesion. This is hypothesized to promote healing of the underlying corneal surface, since drying is reduced by continued corneal coverage, even if the covering layer is thin. Tears H and SU have the highest mucoadhesive properties of the 4 tears, and Figure 2 shows they produced higher and longer sustained changes in contrast sensitivity. 

Previous studies related to residence time of tears note significant variability in the performance of dry eye subjects. This may be a contributing factor to the variability we observed with contrast sensitivity measurement. The investigators suggest that groups of a minimum size of 15 are required to differentiate adequately on-eye performance of different artificial tear formulations. Our results support that notion. ¹¹  

As noted above, contrast sensitivity was quite variable. More sensitive, and less variable, measures of visual optics, such as dynamic wavefront aberrometry, may provide a better way to measure the shorter term effects of artificial tears on dry eye patients. ²³ If contrast sensitivity is being measured, a concurrent measure of artificial tear residence time also might help better define the effects of the various treatments. 

In summary, our study suggested that the effects of artificial tears on measured contrast sensitivity in dry eye patients in the postinstillation period of 5 minutes to 4 hours are limited, but that an artificial tear with more mucoadhesive properties, demonstrating a greater affinity for the corneal epithelium, may have more benefit than those that do not. Modest effects on contrast sensitivity, primarily at medium spatial frequencies, were observed with the more mucoadhesive formulations. Future studies with larger sample sizes, and additional measures of tear residence time and dynamic aberrometry may be helpful to characterize better the visual benefits of artificial tears in the short-term (5 minutes to 4 hours) time frame. 

Acknowledgments

Supported by unrestricted funding from Alcon (China) Ophthalmic Product Co., Ltd, Beijing, China, for data analysis and manuscript preparation (RP). The authors alone are responsible for the content and writing of the paper. 

Disclosure: Y. Zhang, None; R. Potvin, Alcon (China) Ophthalmic Product Co., Ltd. (F, C, R); L. Gong, None